Cervical cancer in Foods Points of View

Kyle J. Norton(Draft Article)

Cervix is the lower part of uterus that opens at the top of the vagina. Cervix acts an transition area for vaginal lining (squamous epithelium) change to uterus type (columnar epithelium) through the transitional area (squamous columnar epithelium) to host the development of the fetus. Cervical cancer is malignant neoplasm of the cervix uteri or cervical area caused by abnormal cells growth with alternation of cells DNA. According to the American Cancer Society's, in 2014, 12,360 new cases of invasive cervical cancer will be diagnosed with the death of  4,020 patients. The risk of cervical cancer is higher in Hispanic women followed by African-Americans, Asians and Pacific Islanders, and whites(a).
Depending to the stage and grade of the cancer, if the cancer is found in the early stahe, hysterectomy may not be needed. Other while  after sugery, chemotherapy including Cisplatin, Fluorouracil (5-FU), Mitomycin, Paclitaxel, Ifosfamide, Carboplatin, Bevacizumab and radiotherapy may be necesary, but with certain side effects.  emerging suggestion of a healthy and balanced diet to improve high serum levels of antioxidants may reduce cervical neoplasia risk(b)(c)  but other suggested that the role of diet and nutrition in the etiology of cervical cancer is not yet resolved(d) and Catalan Institute of Oncology study showed statistically nonsignificant inverse associations were also observed for leafy vegetables, root vegetables, garlic and onions, citrus fruits, vitamin C, vitamin E and retinol for invasive squamous cervical cancer (ISC)(e).

Epidemiological studies, linking foods in reduced risk of cerical cancer have been inconsistent. but certain foods have found effectively in reduced risk and treatment of cervical cancer.

1. Cruciferous vegetablesCruciferous vegetables are the group of vegetables belonging to the family Brassicaceae, including cauliflower, cabbage, cress, bok choy, broccoli etc.
Isothiocyanates, a majpr chemical constituent found in Cruciferous vegetables, inhibited the cell viability of human cervical cancer cells, through improvement of antioxidant status(1). β-Phenylethyl isothiocyanate (PEITC). induced apoptosis to inhibit cell proliferation in human cervical cancer cell lines (HEp-2 and KB), through increased the expression of the death receptors (DR4 and DR5) and cleaved caspase-3(2).  Other chemical compouds,  I3C (indole-3-carbinol) and DIM (diindolylmethane) found in all types of cruciferous vegetables, demonstrated exceptional anti-cancer effects against hormone responsive cancers such as ovarian cancers(3). Some reseachers suggested that isothiocyanates and indoles through intake of cruciferous vegetable consumption may decrease cancer risk, but the protective effects may be influenced by individual genetic variation (polymorphisms) in the metabolism and elimination of isothiocyanates from the body and in some in instances, long term rxposure to sulforaphane and indole-3-carbinol (I3C), may be implicated in a variety of anticarcinogenic mechanisms(4).

2. Tomato
Tomato is a red, edible fruit, genus Solanum, belonging to family Solanaceae, native to South America. Because of its health benefits, tomato is grown world wide for commercial purpose and often in green house.
Glycoalkaloid-rich green tomato extracts, according to the Seowon University inhibited ptofileration of HeLa cervical carcinoma cells through inactivation(5). Dr Ferguson LR, in the study of Prospects for cancer prevention, suggested that Fruit and vegetable servings should total a minimum of five each day. Some specific fruits and vegetables (e.g., tomato, broccoli, onions) may have particular benefits against individual cancer types(6). But the reviews of FDA in 2004, of some studies of indication of an inverse association between tomato and/or lycopene intake and the risk of some types of cancer, suggested that there are no credible evidence for an association between tomato consumption and a reduced risk of lung, colorectal, breast, cervical, or endometrial cancer(7).

3. Garlic
Garlic is a natural superfood healer for its natural antibiotic with antiviral, antifungal, anticoagulant and antiseptic properties.
Diallyl sulfide (DAS), a chemical component of garlic induced mitochondrial dysfunction, leading to the release of cytochrome c for causing apoptosis in human cervical cancer Ca Ski cells(8) and cell cycle arrest and apoptosis through the p53, caspase- and mitochondria-dependent pathways in in HeLa human cervical cancer cells(9). The Defense Food Research Laboratory study indicated that Garlic exerted its anticarcinogenic effect(including cervical cancer) through a number of mechanisms, including scavenging of radicals, increasing gluathione levels, increasing the activities of enzymes(10). In 3-methylcholanthrene (MCA)-induced carcinogenesis in the uterine cervix of virgin young adult Swiss albino mice study, found a sginificant decline in the incidence of carcinoma witjh oral administration of garlic at the dose level of 400 mg/kg body wt./day for 2 weeks before and 4 weeks following carcinogen thread insertion(11).

4. Ginger
Ginger (Zingiber officinale) or ginger root is the genus Zingiber, belonging to the family Zingiberaceae, native to Tamil. It has been used in traditional and Chinese medicine to treat dyspepsia, gastroparesis, constipation, edema, difficult urination, colic, etc.
Crude methanol and fractionated extract of the rhizomes of Alpinia pahangensis, a wild ginger distributed in the lowlands of Pahang, Malaysia, showed potent cytotoxic effect against certain cancer cell lines, including human cervical cancer cell line, Ca Ski(12). In human cervical epithelial carcinoma (HeLa), aqueous extract of ginger (GAE) induced apoptosis of cancer cells through interacted directly with cellular microtubules and disrupts its structure(13). Other study indicated that
Benjakul [BEN], a composeition of five plants: Piper chaba fruit [PC], Piper sarmentosum root [PS], Piper interruptum stem [PI], Plumbago indica root [PL] and Zingiber officinale rhizome [ZO] in Thai herbal medicine, showed to extert its cytotoxic activity against certain types of cnacer cell line including cervial cancer cell line Hela(14).

5. Carrot
Carrot can grow to 3ft tall. It is root vegetable with orange color normally, a sub spices of Daucus carota, belongs to the family Apiaceae, native to Asian and Europe.
According to Aichi Cancer Center, frequent intakes of carrot are associated decreased risk of cervical cancer(15). The Shandong University study in assessing the risk of cervical cancer association of vitamin A found a abundantly in carrot (retinol, carotene and other carotenoids) intake or blood (serum or plasma) levels of vitamin A (retinol and carotene), indicated that vitamin A intake and blood vitamin A levels are inversely associated with the risk of cervical cancer(16). Others in the testing of concentrations of retinol and beta carotene in serum samples taken from 113 women with cervical cancer, 32 with invasive and 81 with pre-invasive disease, and compared with those from 226 age-matched control women found a significantly reduced concentration of beta carotene levels in women with pre-invasive disease compared to the control(17).

6. Dulse
Dulse is a red seaweed of genus Palmaria, belong to Family Palmariaceae that grows attached to rocks by a "holdfast" in the North Atlantic and Northwest Pacific. It is commonly used in Ireland and Atlantic Canada both as food and medicinally and is now shipped around the globe. Dulse is found in many health food stores or fish markets or can be ordered directly from local distributors.
Ryerson University study of the extracts from variety of edible seaweeds, showed a positive effect of dulse polyphenols in inhibited on cell proliferation on human cervical adenocarcinoma cell line (HeLa cells) through its antioxidant activity(18)(19). Fucoxanthin found abundantly in dulse, in the study by Henan University, showed to exert autophagy-dependent cytotoxic effect in cervical cancer cell lines HeLa cells via inhibition of Akt/mTOR signaling pathway(20).

8. Strawberry
Strawberries is a genius of Fragaria × ananassa belongs to the family Roseaceae. They have been grown all over the world with suitable climate for commercial profits and for health benefits.
The study of the effects of variety of berry extracts in human cervical cancer (HeLa) cells, indicated that
tannin-rich fraction of procyanidins of strawberry extract are most potent in comparison with other berries(21). Other study of the effects of the extract of Strawberry, Blueberry, and Raspberry Extracts. showed a positive effects of ethanol extracts from all four fruits strongly inhibited CaSki and SiHa cervical cancer cell lines(22).

9. Grape and Red wine
Grape is a woody vines of the genus Vitis, belong to the family Vitaceae, native to southern Turkey. Grape extracts was found to interact effectively with decaffeinated green tea extracts both in the inhibition of tNOX activity and in the inhibition of cancer cell growth(23). Red and white wine polyphenols and resveratrol exerted higher cytotoxic activity against HeLabut white wine polyphenolic extract exhibited a significantly higher antiproliferative action on cancer cell lines than red wine extract(24).

10. Cactus pear
Cactus pear also known as Prickly pear is a genus Opuntia, belonging to the family Cactaceae, native to Mexico.
Cactus pear extracts, in the study of immortalized ovarian and ovarian cancer cells (OVCA420, SKOV3), exhibited anti ptoliferative effect through a dramatic increase of reactive oxygen species (ROS), induced DNA fragmentation, together with a perturbed expression of apoptotic-related (Bax, Bad, caspase 3, Bcl2, p53, and p21) and ROS-sensitive (NF-kappaB, c-jun/c-fos) genes(25). Other study from the University of Arizona, indicated that aqueous extracts of cactus pear significant increase in apoptosis and growth inhibition in both immortalized epithelial cells and cancer cells in a dose- and time-dependent manner through cell cycle arrest(26).

11.  Vitis coignetiae Pulliat
Vitis coignetiae Pulliat also known as Yamabudo, Crimson Glory Vine, is the genus Viti, belonging to the family Vitaceae, native to the temperate climes of Asia. It has been used as a health juice and wine because of the abundant polyphenols and anthocyanins.
Anthocyanins from fruits of Vitis coignetiae Pulliat (AIMs), inhibited the invasion of HeLa cell in a dose-dependent manner, through suppressing NF- κ B-regulated genes and EMT, which relates to suppression of I κ B α phosphorylation and GSK-3 activity(26). In stem extracts from Greek Vitis vinifera varieties of the total polyphenolic content (TPC) found to  stem extracts inhibited at low concentrations the growth of HepG2 and HeLa cancer cells comparable to those of seed extracts(27)(28).

12. Fatty fish
Fatty fish containing a large amounts of omega-3, 6 fatty acids may be associated to reduced risk of cancers. Docosahexaenoic acids (DHA) found in fish oil plays important roles in reduced the progression of carcinogenesis, including human cervical cancer cell line, HeLa(29), through cytotoxic effects(30). Unluckily, n the study of the relationship between dietary fat and cancer, researchers at the Fred Hutchinson Cancer Research Center, indicated that fish omega-3 polyunsaturated fat had a nonsignificant negative association with the cancer(31)

13. Green Tea
Green tea contains more amount of antioxidants than any drinks or food with the same volume, and is the leaves of Camellia sinensis, undergone minimal oxidation during processing, originated from China. Green tea has been a precious drink in traditional Chinese culture and used exceptional in socialization for more than 4000 thousand years. Because of their health benefits, they have been cultivated for commercial purposes all over the world.
In a total of  104 patients diagnosed with cervical cancer or cervical intraepithelial neoplasias (CINII/III)936 healthy women selected from the Wufeng area, showed a positive effect of green tea in reduced risk of Green tea intake in cervical cancer or CINII/III(32).  (-)-epigallocatechin-3-gallate (EGCG), a major chemical compound in green tea, inhibited the proliferation of human cervical cancer cell line, CaSki through induction of apoptosis and cell cycle arrest as well as regulation of gene expression(33). In other huamun cervical cancer cell line,  HeLa, (-)-epigallocatechin-3-gallate (EGCG), showed it anti proliferative effects through reduced mRNA expression of FTS via p53(34).

14. Organic soybean
Soybean is genus Glycine, the family Fabaceae, one of the legumes that contains twice as much protein per acre as any other major vegetable or grain crop, native to Southeast Asia. Now, it is grown worldwide with suitable climate for commercial profit and a healthy foods.
In female athymic mice, germinated soy protein inhibited the proliferation of cervical cancer cell line HeLa,  through generation of biologically active peptides(35). via down-regulated PTTG1 and TOP2A mRNA expression (two genes considered as therapeutic targets) and induced apoptosis in cancer cells(36). Isoflavones , the major bioactive compounds found in organic soy,  the derived isoflavone mixture(SI-I) containing 71% daidzein, 14.3% genistein and 14.7% glycitein inhibited  HeLa cell growth through inducing apoptosis via the mitochondrial pathway(37).

Taking altogether, without going into reviews, the list of foods above may be potent in reduced risk and treatment of cervical cancer. But further studies with large sample sizes and multi centers are necessary to improve the validation of these claims. As always, all articles written by Kyle J. Norton are for information & education only, please consult your Doctor & Related field specialist before applying
 
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References
(a) Cerical cancer (Amerrican cancer society)
(b) Diet and serum micronutrients in relation to cervical neoplasia and cancer among low-income Brazilian women by Tomita LY¹, Longatto Filho A, Costa MC, Andreoli MA, Villa LL, Franco EL, Cardoso MA; Brazilian Investigation into Nutrition and Cervical Cancer Prevention (BRINCA) Study Team.(PubMed)
(c) Associations of dietary dark-green and deep-yellow vegetables and fruits with cervical intraepithelial neoplasia: modification by smoking by Tomita LY¹, Roteli-Martins CM, Villa LL, Franco EL, Cardoso MA; BRINCA Study Team.(PubMed)
(d) Diet and the risk of in situ cervical cancer among white women in the United States by Ziegler RG¹, Jones CJ, Brinton LA, Norman SA, Mallin K, Levine RS, Lehman HF, Hamman RF, Trumble AC, Rosenthal JF, et al.(PubMed)
(e) Dietary factors and in situ and invasive cervical cancer risk in the European prospective investigation into cancer and nutrition study by González CA¹, Travier N, Luján-Barroso L, Castellsagué X, Bosch FX, Roura E, Bueno-de-Mesquita HB, Palli D, Boeing H, Pala V, Sacerdote C, Tumino R, Panico S, Manjer J, Dillner J, Hallmans G, Kjellberg L, Sanchez MJ, Altzibar JM, Barricarte A, Navarro C, Rodriguez L, Allen N, Key TJ, Kaaks R, Rohrmann S, Overvad K, Olsen A, Tjønneland A, Munk C, Kjaer SK, Peeters PH, van Duijnhoven FJ, Clavel-Chapelon F, Boutron-Ruault MC, Trichopoulou A, Benetou V, Naska A, Lund E, Engeset D, Skeie G, Franceschi S, Slimani N, Rinaldi S, Riboli E.(PubMed)
(1) The anti-oxidant properties of isothiocyanates: a review by de Figueiredo SM¹, Filho SA, Nogueira-Machado JA, Caligiorne RB.(PubMed)
(2) Effect of β-phenylethyl isothiocyanate from cruciferous vegetables on growth inhibition and apoptosis of cervical cancer cells through the induction of death receptors 4 and 5 by Huong le D¹, Shim JH, Choi KH, Shin JA, Choi ES, Kim HS, Lee SJ, Kim SJ, Cho NP, Cho SD(PubMed)
(3) Chemopreventive properties of indole-3-carbinol, diindolylmethane and other constituents of cardamom against carcinogenesis by Acharya A¹, Das I, Singh S, Saha T.(PubMed)
(4) Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis by Higdon JV¹, Delage B, Williams DE, Dashwood RH.(PubMed)
(5) Changes in free amino acid, phenolic, chlorophyll, carotenoid, and glycoalkaloid contents in tomatoes during 11 stages of growth and inhibition of cervical and lung human cancer cells by green tomato extracts by Choi SH¹, Lee SH, Kim HJ, Lee IS, Kozukue N, Levin CE, Friedman M.(PubMed)
(6) Prospects for cancer prevention by Ferguson LR.(PubMed)
(7) The U.S. Food and Drug Administration's evidence-based review for qualified health claims: tomatoes, lycopene, and cancer by Kavanaugh CJ¹, Trumbo PR, Ellwood KC.(PubMed)
(8) Diallyl sulfide promotes cell-cycle arrest through the p53 expression and triggers induction of apoptosis via caspase- and mitochondria-dependent signaling pathways in human cervical cancer Ca Ski cells by Chiu TH¹, Lan KY, Yang MD, Lin JJ, Hsia TC, Wu CT, Yang JS, Chueh FS, Chung JG.(PubMed)
(9) Diallyl sulfide induces cell cycle arrest and apoptosis in HeLa human cervical cancer cells through the p53, caspase- and mitochondria-dependent pathways by Wu PP¹, Chung HW, Liu KC, Wu RS, Yang JS, Tang NY, Lo C, Hsia TC, Yu CC, Chueh FS, Lin SS, Chung JG.(PubMed)
(10) Anticarcinogenic properties of garlic: a review by Khanum F¹, Anilakumar KR, Viswanathan KR.(PubMed)
(11) Chemopreventive action of garlic on methylcholanthrene-induced carcinogenesis in the uterine cervix of mice by Hussain SP¹, Jannu LN, Rao AR.(PubMed)
(12) Antioxidant potential, cytotoxic activity and total phenolic content of Alpinia pahangensis rhizomes by Phang CW¹, Malek SN, Ibrahim H.(PubMed)
(13) Aqueous extract of ginger shows antiproliferative activity through disruption of microtubule network of cancer cells by Choudhury D¹, Das A, Bhattacharya A, Chakrabarti G.(PubMed)
(14) In vitro cytotoxic activity of Benjakul herbal preparation and its active compounds against human lung, cervical and liver cancer cells by Ruangnoo S¹, Itharat A, Sakpakdeejaroen I, Rattarom R, Tappayutpijam P, Pawa KK.(PubMed)
(15) [Hospital epidemiology--a comparative case control study of breast and cervical cancers].

[Article in Japanese] by Tajima K¹, Hirose K, Ogawa H, Yoshida M, Ohta M.(PubMed)

(16) Vitamin A and risk of cervical cancer: a meta-analysis by Zhang X¹, Dai B, Zhang B, Wang Z.(PubMed) 

(17) Cancer of the cervix uteri and vitamin A by Harris RW, Forman D, Doll R, Vessey MP, Wald NJ.(PubMed) 

(18) Antioxidant and antiproliferative activities of extracts from a variety of edible seaweeds by Yuan YV¹, Walsh NA.(PubMed) 

(19) Extracts from dulse (Palmaria palmata) are effective antioxidants and inhibitors of cell proliferation in vitro. by Yuan YV¹, Carrington MF, Walsh NA.(PubMed) 

(20) Essential role of autophagy in fucoxanthin-induced cytotoxicity to human epithelial cervical cancer HeLa cells by Hou LL¹, Gao C, Chen L, Hu GQ, Xie SQ.(PubMed) 

(21) Berry extracts exert different antiproliferative effects against cervical and colon cancer cells grown in vitro by McDougall GJ¹, Ross HA, Ikeji M, Stewart D.(PubMed) 

(22) Anticarcinogenic Activity of Strawberry, Blueberry, and Raspberry Extracts to Breast and Cervical Cancer Cells. by Wedge DE¹, Meepagala KM, Magee JB, Smith SH, Huang G, Larcom LL.(PubMed) 

(23) Anticancer activity of grape and grape skin extracts alone and combined with green tea infusions by Morré DM¹, Morré DJ.(PubMed) 

(24) Cytotoxic effect of wine polyphenolic extracts and resveratrol against human carcinoma cells and normal peripheral blood mononuclear cells by Matić I¹, Zizak Z, Simonović M, Simonović B, Godevac D, Savikin K, Juranić Z.(PubMed)

(25) Cactus pear extracts induce reactive oxygen species production and apoptosis in ovarian cancer cells by Feugang JM¹, Ye F, Zhang DY, Yu Y, Zhong M, Zhang S, Zou C.(PubMed) 

(26) Cactus pear: a natural product in cancer chemoprevention by Zou DM¹, Brewer M, Garcia F, Feugang JM, Wang J, Zang R, Liu H, Zou C.(PubMed)
(27) Anthocyanins from Vitis coignetiae Pulliat Inhibit Cancer Invasion and Epithelial-Mesenchymal Transition, but These Effects Can Be Attenuated by Tumor Necrosis Factor in Human Uterine Cervical Cancer HeLa Cells by Lu JN¹, Lee WS, Yun JW, Kim MJ, Kim HJ, Kim DC, Jeong JH, Choi YH, Kim GS, Ryu CH, Shin SC.(PubMed)
(28) Assessment of polyphenolic content, antioxidant activity, protection against ROS-induced DNA damage and anticancer activity of Vitis vinifera stem extracts by Apostolou A¹, Stagos D, Galitsiou E, Spyrou A, Haroutounian S, Portesis N, Trizoglou I, Wallace Hayes A, Tsatsakis AM, Kouretas D.(PubMed)
(29) Omega-3 but not omega-6 unsaturated fatty acids inhibit the cancer-specific ENOX2 of the HeLa cell surface with no effect on the constitutive ENOX1 by Morre J¹, Morré DM, Brightmore R.(PubMed)
(30) Differential sensitivity of cancer cells to docosahexaenoic acid-induced cytotoxicity: the potential importance of down-regulation of superoxide dismutase 1 expression by Ding WQ¹, Vaught JL, Yamauchi H, Lind SE.(PubMed)
(31) Types of dietary fat and the incidence of cancer at five sites by Hursting SD¹, Thornquist M, Henderson MM.(PubMed)
(32) Case-control study of diet in patients with cervical cancer or precancerosis in Wufeng, a high incidence region in China by  Jia Y¹, Hu T, Hang CY, Yang R, Li X, Chen ZL, Mei YD, Zhang QH, Huang KC, Xiang QY, Pan XY, Yan YT, Wang XL, Wang SS, Hang Z, Tang FX, Liu D, Zhou J, Xi L, Wang H, Lu YP, Ma D, Wang SX, Li S.(PubMed)
(33) A major constituent of green tea, EGCG, inhibits the growth of a human cervical cancer cell line, CaSki cells, through apoptosis, G(1) arrest, and regulation of gene expression by Ahn WS¹, Huh SW, Bae SM, Lee IP, Lee JM, Namkoong SE, Kim CK, Sin JI.(PubMed)
(34) EGCG suppresses Fused Toes Homolog protein through p53 in cervical cancer cells by Muthusami S¹, Prabakaran DS, An Z, Yu JR, Park WY.(PubMed)
(35) Effect of germinated soy protein on the growth of HeLa cervical cancer cells in female athymic mice by Robles-Ramírez Mdel C¹, Ramón-Gallegos E, Reyes-Duarte FJ, Mora-Escobedo R.(PubMed)
(36) A peptide fraction from germinated soybean protein down-regulates PTTG1 and TOP2A mRNA expression, inducing apoptosis in cervical cancer cells by Robles-Ramírez Mdel C¹, Ramón-Gallegos E, Mora-Escobedo R, Torres-Torres N.(PubMed)
(37) Soy-derived isoflavones inhibit HeLa cell growth by inducing apoptosis by Xiao JX¹, Huang GQ, Geng X, Qiu HW.(PubMed)